Environmental influence on gametes and embryos

哺乳动物受精的一个普遍特征是，精子在卵中引起一系列重复的钙振荡，持续数小时，并以原核形成终止。小鼠中的这种钙振荡模式对于响应于受精的卵激活的早期事件和发生的足月子宫内发育都是必不可少的。精子内负责诱导这些钙振荡的因子是睾丸特异性磷脂酶C，PLC zeta，其在精卵质膜融合后从精子头部释放，并且在迄今为止研究的所有哺乳动物精子中发现，包括人类。钙的波动也受鸡蛋内因素的控制。正在使用小鼠模型进行研究，以检查卵子内负责控制钙振荡行为和钙再吸收的分子，这些过程对于受精时钙振荡的持续至关重要。我们发现，质膜钙ATP酶是受精时钙信号传导的关键介质，受精时其功能的破坏会影响后代的健康;这项工作已发表。我们还发现，TRPM 7是植入前胚胎成功发育所必需的;这项工作已经提交。由于TRPM 7活性受胚胎培养基中二价阳离子浓度的调节，因此这一发现对辅助生殖过程中培养人类胚胎的环境条件具有重要意义。在我们正在进行的研究中，我们正在确定受精后钙通量调节的其他机制，以及这些通量的改变对后代发育和健康的影响。我们预计，通过更好地了解卵子激活过程中钙振荡行为的分子和细胞调节模式，我们可以了解早期胚胎发育如何被环境因素和疾病状态改变。 许多必需分子由母体mRNA编码，这些mRNA在卵母细胞成熟期间被募集用于翻译，并且对受精和胚胎发育的早期步骤至关重要。这些步骤之一，胚胎基因组激活（EGA），是精心策划的卵母细胞成熟过程中启动的内在发育程序，但我们有一个不完整的理解如何转录机制和/或序列特异性转录因子决定的哺乳动物EGA的时间，并有助于发展潜力。我们发现OBOX家族中的同源框转录因子对于驱动小鼠EGA至关重要;发表了一篇描述这些结果的论文。我们正在进行的工作集中在额外的转录因子在调节EGA的作用。这些研究揭示了暴露于环境化学品可能会破坏的基本遗传过程，并可能影响人类生育能力和其他人类疾病状态。

A universal feature of fertilization in mammals is that the fertilizing sperm evokes a series of repetitive calcium oscillations in the egg that persist for several hours and terminate with pronucleus formation. This pattern of calcium oscillations in mice is essential for both early events of egg activation in response to fertilization and for full term intrauterine development to occur. The factor within sperm responsible for inducing these calcium oscillations is a testis-specific phospholipase C, PLC zeta, which is released from the sperm head after sperm-egg plasma membrane fusion and is found in all mammalian sperm studied to date, including human. Calcium oscillations are also controlled by factors within the egg. Studies are being performed using the mouse model to examine molecules within the egg that are responsible for controlling calcium oscillation behavior and calcium reuptake, processes that are essential for the continuation of calcium oscillations at fertilization. We found that plasma membrane calcium ATPases are critical mediators of calcium signaling at fertilization and that disruption of its function at fertilization impacts offspring health; this work was published. We also found that TRPM7 is required in the preimplantation embryo for successful development; this work has been submitted. Because TRPM7 activity is modulated by the concentration of divalent cations in embryo culture medium, this finding has important implications for the environmental conditions under with human embryos are cultured during assisted reproduction procedures. In our ongoing studies, we are determining additional mechanisms by which calcium fluxes are regulated following fertilization and the impact of alterations in these fluxes on offspring development and health. We anticipate that by achieving a better understanding of the molecular and cellular modes of regulation of calcium oscillatory behavior during egg activation, we can learn how early embryo development is altered by environmental factors and by disease states. Many essential molecules are encoded by maternal mRNAs that are recruited for translation during oocyte maturation and critically important for fertilization and the early steps of embryonic development. One of these steps, embryonic genome activation (EGA), is orchestrated by an intrinsic developmental program initiated during oocyte maturation, but we have an incomplete understanding of how the transcriptional machinery and/or sequence-specific transcription factors dictate the timing of EGA in mammals and contribute to developmental potential. We found that homeobox transcription factors in the OBOX family are essential for driving EGA in the mouse; a paper describing these results was published. Our ongoing work is focused on the role of additional transcription factors in regulating EGA. These studies shed light on basic genetic processes that can be disrupted by exposure to environmental chemicals and could impact human fertility and other human disease states.